Men with a family history of prostate cancer have a two to four-fold excess risk of developing prostate cancer compared to those with no family history. The degree of risk elevation associated with familial prostate cancer may depend on several factors including the age at diagnosis of the affected family members and the total number of affected first and/or second-degree relatives. Many multiplex prostate cancer families have been studied over the last decade with the goal of identifying highly penetrant prostate cancer genes using linkage approaches, however, many of these prostate cancer genes remain elusive. An alternative strategy for the identification of prostate cancer susceptibility genes is the use of association studies, which have generally used case:control datasets to study low penetrance genes. The University of Michigan Prostate Cancer Genetics Project (PCGP) is a family-based study with the goal of characterizing the molecular basis for the inherited predisposition to prostate cancer. We hypothesize that prostate cancer susceptibility loci with modest penetrance can also be identified and characterized using family-based association studies. Since prostate cancer is a late-onset disease, and parental genotype information from parents is typically unavailable, we will focus primarily on understanding the genetic differences between men with prostate cancer and their unaffected male siblings. Therefore, to characterize prostate Cancer susceptibility genes using prostate cancer families, the following three Specific Aims are proposed: 1.To ascertain, characterize, and classify sibling pairs discordant for prostate cancer from the University of Michigan Prostate Cancer Genetics Project (PCGP). 2. To identify one or more genes that associate with the generalized risk of prostate cancer among discordant sibling pairs (DSPs) from the PCGP. a. To characterize genes that associate with the diagnosis of early-onset and/or hereditary prostate cancer among the DSPs. b. To study genes that associate with the development of clinically advanced prostate cancer (i.e., high stage and/or high grade) among the DSPs. The translational goal of our project is to identify genes that can be used to determine risk of prostate cancer as well as clinically aggressive prostate cancer in unaffected men with a family history of prostate cancer.